The chemical species, (3S)-2-[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4tetrahydro-3-isoquinolinecarboxylic acid is known generically as quinapril. Its pharmaceutically acceptable salts, specially the hydrochloride salt is represented by formula (I).

Quinapril hydrochloride (I) and its pharmaceutically acceptable salts are active as angiotensin converting enzyme (ACE) inhibitors and thus are commercially valuable antihypertensive agents.
U.S. Pat. No. 4,344,949 (Hoefle et. al.) inter alia describes a process for the preparation of quinapril hydrochloride comprising reaction of ethyl ester of (S,S)-α-[(1-carboxyethyl)aminio] phenylbutanoic acid with the benzyl or t-butyl ester of (S)-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid in the presence of 1-hydroxy benzotriazole, employing standard peptide bond forming methods.
The benzyl or t-butyl ester group of quinapril thus obtained is removed by catalytic hydrogenation or by treatment with trifluoroacetic acid. Quinapril hydrochloride is isolated either by solvent precipitation with diethyl ether or by lyophilisation of the aqueous solution.
The above method is summarised in scheme (I).

Other methods for preparation of quinapril hydrochloride are disclosed by Barton et. al. in GB Patent No. 2,095,252, by Patchett et. al. in EP Patent No. 0,065,301 etc.
However, all the reported methods for synthesis of quinapril suffer from a serious drawback in that the product obtained by all the methods is invariably contaminated with varying amounts of an impurity identified as the diketopiperazine derivative of formula (II), leading, most often to product not conforming to pharmacopoeial specifications.
The diketopiperazine impurity is formed either during removal of the carboxylic acid protective group or it could be formed during drying of quinapril hydrochloride.

The above impurity once formed is difficult to remove by conventional separation techniques, including fractional crystallization.
Regulatory authorities all over the world are becoming very stringent about the purity of an approved drug or a drug candidate awaiting approval. Especially there is a growing concern about the nature and level of impurities present in such molecules.
Pharmaceutical manufacturers throughout the world, constantly strive to produce drug molecules that go beyond pharmacopoeial specifications i.e. compounds having extra pharmacopoeial specifications.
U.S. Pat. No. 4,761,479 (Goel et. al.) discloses a method wherein quinapril hydrochloride obtained from the reaction mixture is crystallized from a solvent selected from acetonitrile or acetone to give a crystalline form of quinapril hydrochloride possessing a characteristic X-ray (powder) diffraction pattern and high bulk density.
The abovementioned patent also mentions that the crystalline material thus obtained contains equimolar amounts of acetonitrile/acetone as part of the crystal lattice. The patent further mentions that the solvent(s) present in the crystal structure can be removed under vacuum at a temperature of about 50° C. However during this unit operation the crystallinity of the substance is lost due to desolvation during drying, and an amorphous material is obtained which is claimed to be free of impurities, specially the diketopiperazine compound of formula (II).
Even though, the U.S. Pat. No. 4,761,479 discloses the use of acetonitrile and acetone for crystallization, the former is preferred since, unlike acetonitrile, acetone cannot be removed from the crystal lattice, even on prolonged drying.
Canadian Application No. CA 2,293,705 A1 (Llagostera et. al) describes a process for purification of impure quinapril hydrochloride through a two-step process, comprising first crystallisation of the impure material from toluene followed by another crystallization using a class III solvent as categorized by International Conference of Harmonisation (ICH). The patent also mentions that initially a solvate of quinapril hydrochloride with toluene is formed, which is subsequently substituted by a solvate of the class III solvent used for the second crystallisation. This patent like the aforesaid U.S. Pat. No. 4,761,479 also claims that amorphous quinapril hydochioride is obtained on desolvation of the solvate of the material with the class III solvent through drying. Among the class III solvents disclosed, ethyl formate and methyl acetate are the preferred ones.
However, the abovementioned two methods for purification of impure quinapril hydrochloride utilise solvents which have low flash points eg. the flash point of acetonitrile is 2° C., that of methyl acetate is −16° C., whereas that of ethyl formate is −20° C., rendering their use on commercial scale a hazardous proposition. Moreover, the method disclosed in the later patent i. e. Canadian Application No. 2,293,705 A1 involves a two-step purification, which makes the entire operation not only time consuming but costly.
The need, therefore, exists for a method for obtaining quinapril hydrochloride of high purity which addresses the shortcomings associated with the prior art methods.